RT Journal Article
SR Electronic
T1 The use of physiology-based PK and PD modeling in the discovery of the dual orexin receptor antagonist ACT-541468
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.241596
DO 10.1124/jpet.117.241596
A1 Treiber, Alexander
A1 de Kanter, Ruben
A1 Roch, Catherine
A1 Gatfield, John
A1 Boss, Christoph
A1 von Raumer, Markus
A1 Schindelholz, Benno
A1 Muehlan, Clemens
A1 van Gerven, Joop
A1 Jenck, Francois
YR 2017
UL http://jpet.aspetjournals.org/content/early/2017/07/07/jpet.117.241596.abstract
AB The identification of new sleep drugs poses particular challenges in drug discovery due to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging in case inter-species differences are prominent. This report describes the discovery of the dual OX1 and OX2 receptor antagonist ACT-541468 out of a class of structurally related compounds by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied already early in drug discovery. While all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large inter-species differences in key factors determining their pharmacokinetic profile. Human PK models were built based on in vitro metabolism and physico-chemical data, and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated based on OX2 receptor occupancy thresholds of about 65% derived from clinical data of two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery therefore has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.